Neural Crest-Specific Loss of <i>Prkar1a</i> Causes Perinatal Lethality Resulting from Defects in Intramembranous Ossification

Jones, Georgette N.; Pringle, Daphne R.; Yin, Zhirong; Carlton, Michelle M.; Powell, Kimerly; Weinstein, Michael; Toribio, Ramiro E.; Perle, Krista M. D. La; Kirschner, Lawrence S.

doi:10.1210/jcem.95.7.9993

Cited by 6 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These findings show that loss of Prkar1a impaired osteoblastic differentiation in three cell models, which is consistent with our previous report showing that cell differentiation is altered in Prkar1a tissue-specific knockout animals (8).…”

Section: Stable Knockdown Of Prkar1a Results In Impaired Osteoblasticsupporting

confidence: 94%

“…At the biochemical level, loss of this regulatory subunit of PKA leads to enhanced PKA activity in all systems studied (5)(6)(7). In our previous studies, we reported that Prkar1a ϩ/Ϫ mice (the genetic model for human patients) develop tumors in multiple cell lineages, including neural crest cells and osteoblasts (8,9). Based on the failure of Prkar1a knockout neural crest cells to undergo intramembranous ossification (8,9), we proposed that defective terminal differentiation might underlie the phenotype caused by this genetic manipulation.…”

mentioning

confidence: 99%

“…In our previous studies, we reported that Prkar1a ϩ/Ϫ mice (the genetic model for human patients) develop tumors in multiple cell lineages, including neural crest cells and osteoblasts (8,9). Based on the failure of Prkar1a knockout neural crest cells to undergo intramembranous ossification (8,9), we proposed that defective terminal differentiation might underlie the phenotype caused by this genetic manipulation. Others also showed that increased level of cAMP/PKA signaling was related to defective osteogenic differentiation (10,11), potentially due to a role in the stem cell niche (12).…”

mentioning

confidence: 99%

See 2 more Smart Citations

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

Zhang

Manchanda

et al. 2014

Molecular Endocrinology

Self Cite

View full text Add to dashboard Cite

PRKAR1A is the gene encoding the type 1A regulatory subunit of protein kinase A, and it is the cause of the inherited human tumor syndrome Carney complex. Data from our laboratory has demonstrated that Prkar1a loss causes tumors in multiple cell lineages, including neural crest cells and osteoblasts. We have proposed that one mechanism by which tumorigenesis occurs is through the failure of terminal differentiation. In the present study, we directly test the effects of Prkar1a reduction on osteogenic differentiation in mouse and human cells in vitro. We found that Prkar1a levels noticeably increased during osteoblastic differentiation, indicating a positive correlation between the expression of Prkar1a and osteogenic potential. To validate this hypothesis, we generated stable Prkar1a knockdown in both mouse and human cells. These cells displayed significantly suppressed bone nodule formation and decreased expression of osteoblast markers such as osteocalcin and osteopontin. These observations imply that the antiosteogenic effect of Prkar1a ablation is not species or cell line specific. Furthermore, because Runt-related transcription factor-2 (Runx2) is a key mediator of osteoblast differentiation, we reasoned that the function of this transcription factor may be inhibited by Prkar1a knockdown. Chromatin immunoprecipitation and luciferase assays demonstrated that Prkar1a ablation repressed DNA binding and function of Runx2 at its target genes. Additionally, we determined that this effect is likely due to reductions in the Runx2-cooperating transcription factors forkhead box O1 and activating transcription factor 4. Taken together, this study provides direct evidence that ablation of Prkar1a interferes with signaling pathways necessary for osteoblast differentiation.

show abstract

Section: Stable Knockdown Of Prkar1a Results In Impaired Osteoblasticsupporting

confidence: 94%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Knockdown of PRKAR1A, the Gene Responsible for Carney Complex, Interferes With Differentiation in Osteoblastic Cells

Zhang

Manchanda

et al. 2014

Molecular Endocrinology

Self Cite

View full text Add to dashboard Cite

show abstract

“…A subpopulations of postmigratory CNC have roles in patterning distinct derivatives, such as Hoxa2 (Tavella and Bobola, 2010) acts as a selector gene for patterning of branchial arch structures, and cAMP-dependent protein kinase (protein kinase A (PKA)) has strict regulation on the derivative patterning (Jones et al, 2010). How these genes and signaling pathways work dynamically and directionally in neural crest migration are intriguing.…”

Section: Neural Crest Migrationmentioning

confidence: 99%

Contribution of cranial neural crest cells to mouse skull development

Wu¹,

Chen²,

Tian³

et al. 2017

Int. J. Dev. Biol.

View full text Add to dashboard Cite

The mammalian skull vault is a highly regulated structure that evolutionally protects brain growth during vertebrate development. It consists of several membrane bones with different tissue origins (e.g. neural crest-derived frontal bone and mesoderm-derived parietal bone). Although membrane bones are formed through intramembranous ossification, the neural crest-derived frontal bone has superior capabilities for osteoblast activities and bone regeneration via TGF, BMP, Wnt, and FGF signaling pathways. Neural crest (NC) cells are multipotent, and once induced, will follow specific paths to migrate to different locations of the body where they give rise to a diverse array of cell types and tissues. Recent studies using genetic mouse models have greatly advanced our knowledge of NC cell induction, proliferation, migration and differentiation. Perturbations or disruptions of neural crest patterning lead to severe developmental defects or diseases. This review summarizes recent discoveries including novel functions of genes or signaling molecules that are capable of governing developmental processes of neural crest patterning, which may function as a gene regulatory network in controlling skull development. The proposed regulatory network will be important to understand how the signaling pathways and genes converge to regulate osteoblast activities and bone formation, which will be beneficial for the potential identification of molecular targets to prevent or alleviate human diseases or disorders involving defective neural crest development.

show abstract

“…More complex geometries are impossible to visualize in anything but 3D space. Facial development, in which the relatively simple branchial arches develop into the various structures of the face, throat and neck, requires 3D interpretation as reported with micro-CT [28][29][30] and with OPT [31]. Patterning of the limb is similarly complex and requires the coordinated development of tendons, muscles, bones and vasculature and is well shown with OPT [32][33][34].…”

Section: Anatomy and Pattern Visualizationmentioning

confidence: 99%